Formulations for the treatment of ocular surface diseases and related methods

ABSTRACT

Formulations for treating ocular surface diseases, such as dry eye disease, and related methods are disclosed. The formulations include and effective amount of ambroxol or a chemical derivative thereof (for example, bromhexine) that may be dispersed in a carrier and may optionally include a biocompatible polymer to provide extended release properties.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. application Ser. No.15/809,659, filed on Nov. 10, 2017, which claims priority to U.S.Provisional Application Ser. No. 62/421,822, filed Nov. 14, 2016, and62/463,717, filed Feb. 26, 2017, the contents of all of which areincorporated by reference herein.

BACKGROUND OF THE INVENTION

The ocular surface of the eye is a complex biological region thatmaintains corneal clarity, regulates tear film, and protects the eyefrom intrusions. Ocular surface diseases and disorders negatively affectthe surface of the eye, including the cornea and the tear film. Ocularsurface diseases include Dry Eye Disease (DED), chronic DED, otherwiseknown as “chronic dry eye syndrome,” “dry eye syndrome,” or“keratoconjunctivitis sicca.” Symptoms of DED include unclear vision,irritation, itching, dryness, burning, light sensitivity, and possibleloss of vision due to ocular surface damage. An estimated 3.2 millionwomen and 1.68 million men aged 50 and over in the United States areaffected by DED. The overall annual burden on the U.S. healthcare systemfrom DED is estimated to be approximately $3.84 billion and the totalestimated cost of DED on the population of the U.S. is estimated to beapproximately $55.4 billion. The prevalence of DED increases linearlywith age and appears to be higher in Asian populations.

SUMMARY OF THE INVENTION

Currently, dry eye is considered a multifactorial disease of the ocularsurface characterized by a loss of homeostasis of the tear film, andaccompanied by ocular symptoms, in which tear film instability andhyperosmolarity, ocular surface inflammation and damage, andneurosensory abnormalities play etiological roles. Formulations andmethods of use are disclosed herein to treat ocular surface diseases,such as DED, and related conditions. The disclosed formulations includeAmbroxol and/or one or more derivatives thereof, dispersed in a carrier.The carrier may be water-based (for example, a sterile saline solution)and may include various additives, such as lubricants, preservatives,ionic species, pH-adjusting agents, or other desired additives. In someembodiments, the disclosed formulations include at least onebiocompatible polymer dissolved in the carrier to provide extendedrelease of the ambroxol or chemical derivative. Or, biocompatiblepolymer(s) impregnated with the ambroxol or its chemical derivatives asa vehicle provides extended release of the drug. The disclosedformulations are designed for topical application to the eye and maytake the form of a solution, gel, drop, ointment, suspension,microemulsion, nanoparticulate dispersion, liposome, lotion, and/orpaste, etc. The formulations described herein can be applied to the eyein any suitable manner, such as manually (for example, with eye drops)or with a device that controllably releases the formulation over apredetermined period of time.

DETAILED DESCRIPTION

The current clinical approach to treating DED includes topicalapplication of lubricants for mucosa protection, procedures to slow teardrainage (for example, punctal occlusion, whereby punctal plugs areinserted into the tear drainage canal of the eye to prolong tearresidence time), therapies to improve meibomian gland function in thelid to retard the evaporation of tears, eye shields (such as in the formof moisture chamber for the eyes), and administering anti-inflammatoryagents. Outside the United States, treatment for DED also can includestimulating water secretion and/or mucus secretion in the eye.

However, a large portion of DED patients remains in whom currentclinical approaches generally do not provide sufficient symptom relief.Additionally, ongoing treatment efforts (for example, frequent andregular use of eye drops) can be tedious, demanding (relative to routinebusy daily schedules) and expensive. Various formulations for topicalapplication to the eye for the treatment of DED and related symptoms aredescribed herein. The disclosed formulations and related methods differfrom previous treatment approaches. Specifically, the formulationsdisclosed herein include compounds capable of stimulating theconjunctiva (the mucosal membrane covering the eyeball and the eyelidsurface), which studies indicate can contribute to the maintenance oftear film homeostasis on the ocular surface such as in regulating thequantity and quality of tear film.

The disclosed formulations may improve and, in some cases, cure ocularsurface diseases, such as DED. The disclosed formulations can beproduced in any suitable form, including but not limited to solutions,gels, drops, creams, ointments, suspensions, dispersions,nanoparticulate dispersions, emulsions, microemulsions, liposomes,pastes, or other desired forms. The disclosed formulations compriseambroxol and/or a derivative thereof. Ambroxol, as referenced herein,has the following chemical formula:

Ambroxol is a commercially available synthetic mucolytic drug that issometimes used to stimulate surfactant synthesis in the lung to treatrespiratory diseases associated with viscid or excessive mucus. Ambroxolis an active ingredient in cough syrup and is also available as atablet, pastille, dry powder sachet, inhalation solution, drop, ampule,and effervescent tablet. Prior to the filing of the subject applicationand its priority documents, there had not been any indication thatambroxol or any of its chemical derivatives would be useful for treatingeye conditions, such as ocular surface disease or DED.

As used herein, the terms “ambroxol derivatives” and “chemicalderivatives of ambroxol” refer to compounds derived from ambroxol,precursor compounds for ambroxol, and salt forms of ambroxol, forexample, the acid addition salt ambroxol hydrochloride[trans-4-(2-amino-3,5-dibromobenzyl amino)cyclohexanol hydrochloride].In some embodiments, more than one form of ambroxol may be included in asingle formulation. For example, in some embodiments, a formulation mayinclude at least a first ambroxol derivative and at least a secondambroxol derivative. In these and other embodiments, the formulation mayalso comprise ambroxol.

In some embodiments, the total concentration of ambroxol and chemicalderivatives thereof (if present) may be between 0.01% and 20% by weightbased on the total weight of the formulation (w/w). In these and otherembodiments, the total concentration of ambroxol and chemicalderivatives thereof (if present) may be between 0.01% and 20% by weightbased on the total volume of the formulation (w/v), preferably between0.02 and 10% (w/v). In preferred embodiments, the total concentration ofambroxol and chemical derivatives thereof in the formulation is between0.5 and 5% (w/v). The disclosed formulations also include a carrier inwhich the ambroxol and/or ambroxol derivative(s) are dispersed. In someembodiments, the carrier may be a buffered saline solution, but also maybe an ointment, gel or paste.

The disclosed formulations may also, in some embodiments, include anextended-release vehicle, such as a biocompatible polymer, dissolved inthe carrier or by itself impregnated with ambroxol to hold the ambroxoland slowly release it into the tear film or onto the ocular surface,preferably for an extended release period of up to six months. Thebiocompatible polymer may be biodegradable or non-biodegradable,depending on desired use and application schedule. Example biocompatiblepolymers that may be used in the disclosed formulations as anextended-release vehicle include but are not limited topoly-2-hydroxyethylmethacrylate (p-HEMA hydrogels),poly(lactic-co-glycolic) acid (PLGA), polycaprolactone (PCL),hydroxypropyl cellulose, Anecortave acetate (AnA), gelatin, and/orcollagen. The inclusion of an extended-release vehicle may, in somecases, allow for less frequent application while still providing relieffrom DED symptoms.

In some embodiments, the disclosed formulations may also include one ormore additives. Additives that may be included in the disclosedformulations include but are not limited to demulcents, preservatives,emollients, ionic species, pH-adjusting agents, and other possibleadditives. Example demulcents that may be used in the disclosedformulations include glycerin, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose, methylcellulose, dextran 70,gelatin, polyethylene glycol 300, polyethylene glycol 400, polysorbate80, polyvinyl alcohol, povidone, etc. Examples of preservatives that maybe used in the disclosed formulations include benzalkonium chloride andother known preservatives, such as chlorobutanol. Emollients may includelanolin preparations, various mineral oils, Omega 3, paraffin, petroleumand waxes. Zinc and or sodium ions may be included in the disclosedformulation as an ionic species, in some embodiments. PossiblepH-adjusting agents that may be used include citrate buffers (e.g.,sodium citrate), borate buffers (e.g., sodium borate), and other acidicor basic compounds. Numerous configurations and variations of additivesmay be used in the disclosed formulations.

Some research studies indicate that osmotically-driven water transportacross conjunctival cell membranes is primarily mediated by waterchannels called aquaporins (AQPs), which maintain tear volume andregulate osmolarity at the ocular surface. In particular, elevation ofAQP5 expression in the conjunctiva has been shown to lead to increasedproduction of Mucin 5AC (MUC5AC), a major gel-forming mucin in tearfilm. Accordingly, agents that stimulate AQPs in the conjunctiva mayalso stimulate mucin secretion. Prior to the filing of the subjectapplication, some research indicated that ambroxol can stimulate theexpression of AQP5 in human airway epithelial cells. See Upregulation ofAQP3 and AQP5 Induced by Dexamethasone and Ambroxol in A459 Cells by Benet al, Respiratory Physiology & Neurobiology 161 (2008) 111-118. Thedisclosed formulations may, in some circumstances, stimulate AQPs andMUC5AC in the conjunctiva, thereby improving or relieving symptoms ofDED. Additionally, Ambroxol and chemical derivatives thereof haveanalgesic as well as anti-inflammatory properties, which may furtherhelp relieve eye discomfort, improve tear film homeostasis and/orrestore ocular surface health. In some cases, treatment with thedisclosed formulations may alleviate DED symptoms, such as unclearvision, irritation, itching, dryness, burning, and/or light sensitivity.

Frequency of topical application to a subject (for example, a human oranimal) may vary between patients. For example, in some circumstances,the disclosed formulations may be applied as frequently as once everyten minutes or as infrequently as once every day. The formulation may beapplied once, twice, three times or more over a period of one day, twodays, three days, four days, five days, or more than five days. In someembodiments where an extended-release vehicle is included in theformulation, the formulation may be topically applied with a frequencyof at least one time a day to one time a week, or one time a month toone time every six months. Frequency of topical application can bedetermined by numerous considerations, including level of symptom reliefprovided, pain relief experienced, as well as other pertinent healthconsiderations, such as possible drug interactions. The disclosedformulations may be administered using any desired technique. Forexample, in some cases, the formulations may be eye drops that areadministered manually by a user. In other cases, the formulations may betopically applied as a gel or ointment directly to a desired region ofthe eye using a swab or other type of applicator. In some embodiments,the disclosed formulations may be delivered using a device designed forimmediate formulation release or extended formulation release. Forexample, in some embodiments, the formulation may be delivered using oneor more of the following devices: external pumps, contact lenses,punctal plugs, muco-adhesive tablets, pills, capsules, pellets,particles, plasters, an ocular insert device, strips placed onto theconjunctiva or cornea, conjunctival inserts or depots, subconjunctival,subtenon, and intravitreal injections, or another suitable types ofdevice.

Efficacy of the formulation in a subject can be assessed by numeroustechniques. For example, a patient may self-report symptom reliefexperienced. In other cases, the eye may be visually assessed orclinical tests, such as the Schirmer's Test, wherein paper strips areinserted into the eye for several minutes to measure tear production,may be used to assess formulation efficacy.

The features and advantages described herein are not all-inclusive and,in particular, many additional features and advantages will be apparentto one of ordinary skill in the art in view of the drawings,specification, and claims. Moreover, it should be noted that thelanguage used in the specification has been selected principally forreadability and instructional purposes, and not to limit the scope ofthe inventive subject matter described herein. The foregoing descriptionof the embodiments of the disclosure has been presented for the purposeof illustration; it is not intended to be exhaustive or to limit theclaims to the precise forms disclosed. Persons skilled in the relevantart can appreciate that many modifications and variations are possiblein light of the above disclosure.

1. A method of treating an ocular surface affected by dry eye disease ora symptom thereof, the method comprising topically administering to theocular surface an effective amount of a formulation comprising ambroxoland/or a salt form of ambroxol.
 2. The method of claim 1, wherein saidformulation comprises ambroxol and/or a salt form of ambroxol in acarrier, said carrier being suitable for topical application to the eyeand selected from the group consisting of one or more of a solution,gel, drop, ointment, suspension, microemulsion, nanoparticulatedispersion, liposome, lotion, and paste.
 3. The method of claim 1,wherein the ambroxol and/or salt form of ambroxol is present in theformulation in a weight percent of between 0.001% and 20% based on totalweight or total volume of the formulation.
 4. The method of claim 1,wherein the formulation is administered to the subject using a devicethat provides continuous application of the formulation.
 5. The methodof claim 2, wherein the formulation is administered to the subject atleast once a day for a period of at least five days.
 6. The method ofclaim 2, wherein the formulation is administered to the subject using adevice that provides continuous application of the formulation.
 7. Themethod of claim 1, wherein the ambroxol and/or salt form of ambroxol ispresent in the formulation in a weight percent of between 0.02% and 10%based on total weight or total volume of the formulation.
 8. The methodof claim 1, wherein the ambroxol and/or a salt form of ambroxol ispresent in the formulation in a weight percent of between 0.5 and 5%based on total weight or total volume of the formulation.
 9. The methodof claim 2, wherein the formulation further comprises a biocompatiblepolymer dissolved in the carrier or ambroxol impregnated within abiocompatible polymer.
 10. The method of claim 9, wherein thebiocompatible polymer is poly-2-hydroxyethylmethacrylate (p-HEMAhydrogels), poly(lactic-co-glycolic) acid (PLGA). polycaprolactone(PCL), hydroxypropyl cellulose, Anecortave acetate (AnA) gelatin, and/orcollagen.
 11. The method of claim 1, wherein the formulation furthercomprises at least one additive, wherein the additive is a demulcent,preservative, emollient, ionic species, pH-adjusting agents, and otheradditives.
 12. The method of claim 2, wherein the formulation furthercomprises at least one additive, wherein the additive is a demulcent,preservative, emollient, ionic species, pH-adjusting agents, and otheradditives.
 13. The method of claim 2, wherein the ambroxol and/or a saltform of ambroxol is present in a weight percent of between 0.001 and 2%based on total weight or total volume of the formulation.
 14. The methodof claim 1, wherein the symptom thereof comprises unclear vision,inflammation, itching, dryness, burning, and/or light sensitivity.
 15. Amethod of treating dry eye disease or a symptom thereof, the methodcomprising topically administering to an ocular surface an effectiveamount of a formulation comprising a chemical derivative of ambroxol,the chemical derivative of ambroxol being selected from the groupconsisting of one or more of bromhexine or a salt of bromhexine.
 16. Themethod of claim 15, wherein said formulation comprises said chemicalderivative of ambroxol in a carrier, said carrier being suitable fortopical application to the eye and selected from the group consisting ofone or more of a solution, gel, drop, ointment, suspension,microemulsion, nanoparticulate dispersion, liposome, lotion, and paste.17. The method of claim 15, wherein the chemical derivative of ambroxolis present in the formulation in a weight percent of between 0.001% and20% based on total weight or total volume of the formulation.
 18. Themethod of claim 15, wherein the formulation is administered to thesubject using a device that provides continuous application of theformulation.
 19. The method of claim 15, wherein the formulation isadministered to the subject at least once a day for a period of at leastfive days.
 20. The method of claim 16, wherein the formulation isadministered to the subject using a device that provides continuousapplication of the formulation.
 21. The method of claim 15, wherein thechemical derivative of ambroxol is present in the formulation in aweight percent of between 0.02% and 10% based on total weight or totalvolume of the formulation.
 22. The method of claim 15, wherein thechemical derivative of ambroxol is present in the formulation in aweight percent of between 0.5 and 5% based on total weight or totalvolume of the formulation.
 23. The method of claim 16, wherein theformulation further comprises a biocompatible polymer dissolved in thecarrier or the chemical derivative of ambroxol impregnated within abiocompatible polymer.
 24. The method of claim 23, wherein thebiocompatible polymer is poly-2-hydroxyethylmethacrylate (p-HEMAhydrogels), poly(lactic-co-glycolic) acid (PLGA). polycaprolactone(PCL), hydroxypropyl cellulose, Anecortave acetate (AnA) gelatin, and/orcollagen.
 25. The method of claim 15, wherein the formulation furthercomprises at least one additive, wherein the additive is a demulcent,preservative, emollient, ionic species, pH-adjusting agents, and otheradditives.
 26. The method of claim 16, wherein the formulation furthercomprises at least one additive, wherein the additive is a demulcent,preservative, emollient, ionic species, pH-adjusting agents, and otheradditives.
 27. The method of claim 15, wherein the chemical derivativeof ambroxol is present in a weight percent of between 0.001 and 2% basedon total weight or total volume of the formulation.
 28. The method ofclaim 15, wherein the symptom thereof comprises unclear vision,inflammation, itching, dryness, burning, and/or light sensitivity.
 29. Acomposition comprising chemical derivative of ambroxol, selected fromthe group consisting of one or more of bromhexine or a salt ofbromhexine, in a weight percent of between 0.001% and 2% based on totalweight or total volume of the formulation and a carrier suitable fortopical application to the eye.
 30. The composition of claim 29, whereinsaid carrier comprises buffered saline.
 31. A composition comprisingambroxol and/or a salt form of ambroxol, in a weight percent of between0.001% and 2% based on total weight or total volume of the formulation,and a carrier suitable for topical application to the eye.
 32. Thecomposition of claim 31, wherein said carrier comprises buffered saline.